The applicant has recently identified the mouse mutant coloboma as a novel animal model of hyperactivity with locomotor activity exceeding 3 times control mice. She has demonstrated that the hyperactivity expressed by coloboma mice is the result of a deletion of the Snap gene. This gene encodes SNAP-25, a neuron-specific protein found in presynaptic nerve terminals that plays a major role in transmitter release. SNAP-25 is a component of the machinery essential for docking and holding synaptic vesicles at the presynaptic membrane in readiness for Ca2+ triggered transmitter exocytosis. Thus, it is though likely that defects in transmitter release cause by a reduction in SNAP- 25 expression results in the expression of hyperactivity. In fact, there appears to be a dopaminergic component to the hyperactivity as the applicant has also identified gross behavioral abnormalities in response to dopamimetics. It is hypothesized that abnormalities in vesicular function result in an increased concentration of cytosolic dopamine leading the unregulated nonexocytotic dopamine release ultimately expressed as hyperactivity. This proposal focuses on Ca2+ mediated transmitter release and dopaminergin function in coloboma mice to isolate the synaptic events giving rise to hyperactivity. The specific aims are: 1) To define abnormalities in vesicular neurotransmitter release. Individual release events will be recorded and drug-induced alterations in release assessed. 2) To assess the contribution of catecholaminergic neurotransmission to the generation of locomotor hyperactivity in coloboma mice. This contribution will be tested through a transgenic rescue experiment by replacing SNAP-25 in only catecholaminergic cells. 3) To identify neurochemical defects in vivo underlying hyperactivity in coloboma mice. These experiments will integrate the cellular defects identified in vitro with a functional analysis in vivo. 4) To determine the cellular mechanisms involved in hyperactivity using classical behavior pharmacology. Using drugs known to affect presynaptic dopamine terminals, including storage, synthesis and release, we will establish a direct link between dopamine terminal dysfunction and hyperactivity via this in vivo assay. The mouse mutant coloboma represents an unprecedented model in which to study the contributions of a single known gene to a complex multifactorial phenotype in humans which includes disorders such as attention deficit hyperactivity disorder and Tourette syndrome.